Markus D Siegelin, MD

I am an Associate Professor of Pathology at Columbia University Medical Center (with tenure). As a physician scientist, my laboratory investigates cell death mechanisms in tumors with the ultimate goal to overcome therapeutic resistance and to identify novel treatment regimens for glioblastoma (the most common primary brain tumor in adults) and other treatment resistant solid malignancies, such as melanoma and triple-negative breast cancers. This research is significant because the development of improved treatments for glioblastoma, which carries a prognosis of only 12-18 months in the presence of the standard of care, is highly critical to serve this patient population. Since these neoplasms display marked heterogeneity, targeting multiple signaling pathways simultaneously for therapy might be efficacious. To accomplish this goal, we have designed pathway-specific rational drug combination therapies that have shown to have a significant impact on tumor growth. Our research has contributed to understanding how tumors reprogram metabolism to evade apoptosis and how to use this knowledge to design novel treatments. Below, I summarize some of our most significant findings, which were published in high-impact journals in the field. Parts of our research served as the foundation for the initiation of clinical trials.

The Warburg-effect (named after the German biochemist Otto Warburg) is a phenomenon observed in malignant tumors, including glioblastomas, characterized by an enhanced utilization of glucose and the production of lactate (glycolysis). This biological process is critical for tumors to fuel synthesis of macromolecules to enable extensive cellular division (growth of tumors). My group has shown that the Warburg Effect is in part facilitated by super-enhancers, which are genomic regions that regulate gene expression and are involved in tumor growth (1). Moreover, we discovered that FDA-approved histone deacetylase inhibitors (HDACi) (e.g. panobinostat and romidepsin) disrupt super-enhancers and thereby reverse the Warburg effect. In turn, glioblastoma cells become more reliant on oxidative energy metabolism, especially fatty acid oxidation, which ultimately allows them to escape from HDACi therapy (1). This happens through up-regulation of two key metabolic transcription factors (PGC1A and PPARD) (1), which are implicated in activation of both cellular respiration and fatty acid oxidation. In turn, genetic abrogation of these transcription factors reverses HDAC-inhibitor resistance and drives HDACi-mediated killing efficacy of glioblastoma cells (1). To this end, my group has demonstrated that combining HDACi with clinically validated inhibitors of fatty acid oxidation reduces glioblastoma growth in a synergistic manner in vitro and in relevant in vivo models (1). From a clinical perspective these findings could serve as a foundation for novel clinical trials, involving HDACi in combination with blockers of fatty acid oxidation. Our findings also provide an explanation as to why single treatments with HDACi has not shown limited clinical efficacy against glioblastomas or other high-grade brain tumors, since following treatment with HDACi glioblastoma metabolism will be reprogrammed and cells can escape therapy by activation of alternate survival pathways (e.g. enhancement of fatty acid oxidation).

High- and low-grade gliomas harbor IDH1 mutations, which may be targeted therapeutically in several ways, e.g. through targeting the enzyme itself or through identification of dependencies that IDH1 mutated cells specifically rely on (but not wild-type cells). Our group has made the significant and unexpected discovery that specific targeting of Bcl-xL, which is a mitochondrial protein that inhibits cells death, leads to substantial growth inhibition and induction of intrinsic apoptosis in gliomas that harbor the IDH1 R132H mutation. In an orthotopic glioblastoma xenograft model expressing mutated IDH1, Bcl-xL inhibition through the clinically validated BH3-mimetic, ABT263, leads to long-term survival without induction of toxicity, suggesting translational relevance for patients (2). Mechanistically, this effect is mediated through a metabolite that specifically is increased in IDH1 mutated gliomas, 2-hydroxyglutarate, which inhibits anti-apoptotic Mcl-1 protein levels.

Glioblastomas harbor amplification in the MET gene and therefore c-MET is a viable drug target. However, resistance occurs quickly. In another recent manuscript from my lab (3) we showed that c-MET inhibitor resistance is due to metabolic reprogramming and that targeting oxidative energy metabolism enhances the efficacy of crizotinib (a c-MET inhibitor) in vitro and in orthotopic mouse models of glioblastoma without induction of toxicity (3). These findings suggest that combining crizotinib with inhibitors of oxidative energy metabolism might be beneficial in patients, suffering from glioblastoma.

We have recently made a surprising discovery related to Aurora kinase A (a protein that phosphorylates substrates to regulate cell division) in model systems of glioblastoma and found that Aurora kinase A regulates the Warburg-effect (see above for a description) by stabilizing c-Myc protein levels (a well-known strong facilitator of tumor cell glycolysis). Once Aurora kinase A is inhibited or lost the c-Myc protein is degraded in a manner reliant on another kinase, called GSK3B. In turn, we discovered that c-Myc blocks the expression of a driver of oxidative energy metabolism (PGC1A) by directly binding to the promoter region of PGC1A (4). Therefore, loss of Aurora kinase A (either genetically or through clinically validated inhibitors) leads to a reduction of c-Myc and an increase of PGC1A, resulting in activation of oxidative energy metabolism in glioblastoma model systems (4).

In addition to the studies above, which are based on drug induced metabolic reprogramming, we have focused our attention on general fuel sources/requirements of glioblastoma cells in vitro and in vivo (5). We have made an exciting observation, demonstrating that glioblastoma cells utilize lactate for energy generation in a substantial manner. Notably, in some glioblastoma model systems lactate oxidation is dominant over glucose oxidation as demonstrated by carbon tracing experiments. This finding came as a surprise since in general lactate is considered as a metabolic waste product. We found that the transporter responsible for cellular uptake of lactate is elevated in glioblastoma tissues as compared to normal brain and that targeting MCT1 abrogates lactate metabolism in glioblastoma models. Moreover, we unraveled that lactate is an epigenetic metabolites that appears to affect histone acetylation and in turn regulates gene expression (5).